Abstract
In adapting to disease and loss of tissue, the heart shows great phenotypic plasticity that involves changes to its structure, composition and electrophysiology. Together with parallel whole body cardiovascular adaptations, the initial decline in cardiac function resulting from the insult is compensated. However, in the long term, the heart muscle begins to fail and patients with this condition have a very poor prognosis, with many dying from disturbances of rhythm. The surviving myocytes of these hearts gain Na(+) , which is positively inotropic because of alterations to Ca(2+) fluxes mediated by the Na(+) /Ca(2+) exchange, but compromises Ca(2+) -dependent energy metabolism in mitochondria. Uptake of Ca(2+) into the sarcoplasmic reticulum (SR) is reduced because of diminished function of SR Ca(2+) ATPases. The result of increased Ca(2+) influx and reduced SR Ca(2+) uptake is an increase in the diastolic cytosolic Ca(2+) concentration, which promotes spontaneous SR Ca(2+) release and induces delayed afterdepolarisations. Action potential duration prolongs because of increased late Na(+) current and changes in expression and function of other ion channels and transporters increasing the probability of the formation of early afterdepolarisations. There is a reduction in T-tubule density and so the normal spatial arrangements required for efficient excitation-contraction coupling are compromised and lead to temporal delays in Ca(2+) release from the SR. Therefore, the structural and electrophysiological responses that occur to provide compensation do so at the expense of (1) increasing the likelihood of arrhythmogenesis; (2) activating hypertrophic, apoptotic and Ca(2+) signalling pathways; and (3) decreasing the efficiency of SR Ca(2+) release.